Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer
Introduction
The immune system is highly specialized to recognize non-self-pathogens or tissues and efficiently eliminate them, but tumors can often escape host immunity in various ways. Accumulating evidence in tumor immunology has revealed that tumors generate an immunosuppressive microenvironment that protects the tumor from host immunity, promotes tumor growth, and attenuates immunotherapeutic efficacy [1], [2]. The molecular mechanisms underlying tumor-induced immunosuppression include the generation of regulatory T cells (Treg), impairment of dendritic cell (DC) function, and production of immunosuppressive cytokines, such as IL-10 and TGF-β [1]. More recently, indoleamine 2,3-dioxygenase (IDO), a tryptophan (Trp)-catabolizing enzyme, has attracted special attention in tumor-induced immunosuppression [3], [4], [5], [6], [7], [8], [9]. IDO catalyzes the rate-limiting step of Trp degradation along the kynurenine (Kyn) pathway [5]. Both the reduction in local Trp concentration and production of immunomodulatory Trp metabolites, such as Kyn, by IDO activity potently inhibit T cell proliferation and induce T cell apoptosis, leading to immune tolerance. Surprisingly, recent studies have demonstrated IDO expression in cancer cells as well as tumor-infiltrating antigen-presenting cells (APCs) in tumor tissues, indicating that this molecule is essential for the immune escape of tumor cells [4], [6], [10]. Indeed, IDO expression by tumor cells has been shown to correlate with a poor prognosis in several types of cancers [7], [8], [9].
Recent advances in mass spectrometry enable the simultaneous measurement of Trp and Kyn in human serum or plasma using liquid chromatography/electrospray ionization tandem mass spectrometry (LC–ESI/MS/MS). In human serum or plasma, the IDO activity can be estimated by the Kyn-to-Trp ratio (Kyn/Trp ratio), because Kyn is the first product formed through catabolizing Trp, which is tightly regulated by IDO. To date, several studies have shown that the Kyn/Trp ratio increases in the serum or plasma of patients with cancers, such as malignant melanoma [11] and gynecological cancers [12], suggesting that enhanced IDO activity play a role in immunosuppression observed in cancer patients. However, no data are available about the IDO activity determined from the Kyn/Trp ratio in serum of lung cancer patients using LC–ESI/MS/MS. The present study measured the serum concentrations of Trp and Kyn by LC–ESI/MS/MS and estimated the IDO activity in lung cancer patients. In addition, the correlation between the IDO activity and the clinical parameters of the patients was examined.
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Subjects
One hundred and thirty-six patients with histologically confirmed primary lung cancer were referred to our institutions from 2002 to 2008. Among them, 13 patients were excluded because of chronic renal failure, which increased the serum Kyn/Trp ratio [13], and concomitant cancer other than lung cancers. Thus, a total 123 patients with lung cancer (99 men and 24 women with a mean age of 66.4 ± 10.1 years) were enrolled in the present study. No patients had autoimmune diseases, viral hepatitis, or
Clinical characteristics
The clinical characteristics of the 123 patients with lung cancer and 45 healthy controls are summarized in Table 1. Twenty six patients were classified as early lung cancer, and 97 patients were classified as advanced lung cancer. One hundred and nine patients had non-small cell carcinoma (72 adenocarcinoma, 23 squamous cell carcinoma, 4 large cell carcinoma, 3 adenosquamous cell carcinoma, 7 unclassified carcinoma), while 14 patients had small cell carcinoma.
Serum concentrations of Trp and Kyn
Concentrations of Trp, Kyn, and
Discussion
The present study simultaneously measured the serum concentrations of Trp and Kyn using LC–ESI/MS/MS and calculated the Kyn/Trp ratio to determine the IDO activity in patients with lung cancer. It was found that patients with lung cancer had significantly lower Trp concentrations and higher Kyn concentrations than healthy controls, resulting in significantly higher IDO activity. Moreover, degradation of Trp and increased levels of the IDO activity correlated with disease progression. These data
Conflict of interest
All authors have no conflicts of interest to disclose.
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